Dr Vogiatzi is a Pediatric Endocrinologist with particular interest in the bone disease of thalassemia, a common but poorly understood problem. This is a multidisciplinary project that will take advantage of the expertise of the Hospital for Special Surgery on bone analysis, under the mentorship of Dr Adele Boskey, and the long standing tradition of the Thalassemia Research Program of Weill Medical College on iron metabolism. The proposal describes a 5 year training program for Dr Vogiatzi in the areas of biomechanics, biomineralization, analytical microscopy and bone biology using a mouse model of thalassemia to prepare her for an independent career in the area of bone disease. Specifically, Dr Vogiatzi seeks to examine the pathogenesis of the bone disease in thalassemia and determine new therapeutic regimens using a recently described mouse model of thalassemia. It is hypothesized that the bone loss is thalassemia is associated with ineffective erythropoiesis, improper iron handling and iron chelation, which result in impaired bone formation. The specific aims include the longitudinal characterization of the bone changes in the thalassemic mouse, the study of the effect of ineffective erythropoiesis, iron and iron chelation on bone metabolism and the examination of the effects of a bone anabolic and an antiresorptive agent on the bone abnormalities of thalassemia. Changes in bone metabolism will be determined during normal or low iron diets, with or without the administration of iron dextran. Similar experiments will determine the effect of desferrioxamine, as an iron chelator, parathyroid hormone and alendronate on the bone disease of thalassemia. Bone abnormalities will be identified using histology, microCT, infrared imaging, electron microscopy, chemical analysis and mechanical testing. Bone formation will be studied by determining the effect of the various factors, which are implicated in the pathogenesis of the disease, on osteoblast cell cycle regulation and by performing bone marrow stromal cell cultures. Thalassemia is a congenital anemia that requires treatment with regular transfusions. This research will examine the factors that may cause the bone disease in thalassemia by studying a mouse that has blood and bone abnormalities similar to those seen in patients with the disease. These factors include the anemia itself and increased tissue iron. This study will also determine new medical regimens for the treatment of the bone disease in thalassemia. [unreadable] [unreadable] [unreadable] [unreadable]